Prefrontal cortical deficits are a putative susceptibility factor for PTSD.

Introduction: Only a subset of people who experience a traumatic event develop Post-Traumatic Stress Disorder (PTSD) suggesting that there are susceptibility factors influencing PTSD pathophysiology. While post trauma sequelae factors are extensively studied, susceptibility factors are difficult to study and therefore poorly understood. To address this gap, we previously developed an animal model - Revealing Individual Susceptibility to PTSD-like phenotype (RISP). RISP allows studying susceptibility factors by identifying, before trauma, male rats that are likely to develop a PTSD-like phenotype after trauma. Hypofunctioning prefrontal cortex (PFC) has been reported in people with PTSD, however, it is unclear if it is a susceptibility factor, sequalae factor, or both. Here we tested the hypothesis that male rats classified as Susceptible with RISP will have altered medial prefrontal cortical (mPFC) function prior to a PTSD-inducing trauma. Methods: Experiment 1: Susceptible and Resilient male rats classified with RISP performed spatial exploration and were sacrificed immediately to assess neuronal expression of plasticity-related immediate early genes (Arc and Homer1a) in the medial PFC (mPFC). Experiment 2: Cognitive performance of Susceptible and Resilient rats was evaluated on an attentional set shifting task. Experiment 3: We also analyzed pre-trauma cognitive performance scores of a small group of male military personnel some of whom developed PTSD post-trauma. Results: Experiment 1: Susceptible rats showed altered expression of plasticity-related immediate early genes in the Prelimbic and Infralimbic subregions of the mPFC following spatial exploration. Experiment 2: Susceptible rats showed deficits in attentional set shifting task only when task demands increased. Experiment 3: Male military personnel who developed PTSD post-trauma showed pre-trauma cognitive deficits in a task involving the PFC. Discussion: Susceptible rats showed mPFC deficits both at the cellular and behavioral level before PTSD-inducing trauma. Combined with the findings from the human data, these results support the hypothesis that mPFC deficits in males exist before trauma and thus are a putative susceptibility factor for PTSD. Whether these deficits are a bona fide susceptibility factor will be determined in future studies by testing if enhancing mPFC function in susceptible individuals before trauma will confer resilience to developing PTSD. Building resilience is crucial for minimizing the number of people suffering from PTSD, given that it is difficult to treat and treatments are resource intensive and benefit only a subpopulation of people suffering from PTSD.